Reproductive Years

In 1996, much attention was devoted to genetic mutations that predisposed women to breast and ovarian cancer. In addition, the controversy over cervical screening after total hysterectomy was somewhat put to rest, and the status and progress of women in academic medicine were further described.

BRCA1 Mutations Were Found in Young Patients with Breast Cancer

FitzGerald MG, MacDonald DJ, Krainer M, Hoover I, O'Neil E, Unsal H, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med. 1996; 334:143-9.

In 1994 and 1995, two cancer suppression genes were cloned-BRCA1 on the long arm of chromosome 17 and BRCA2 on chromosome 13. Specific mutations of these genes predispose families to breast and ovarian cancer. Mutations seem relatively rare in the general population; the prevalence is estimated to be 5 to 50 cases per 10 000 persons. In contrast, a BRCA1 mutation that is specific to women of Ashkenazic Jewish descent, the 185delAG mutation, is thought to occur in about 1% of all Jewish women.

What do these mutations mean for patients? On the one hand, women carrying a mutation on BRCA1 have about an 85% risk for developing breast cancer and a 50% risk for developing ovarian cancer by the time they reach 70 years of age. However, women in their 30s who have a mutation carry a risk of approximately 3% over that decade. The incidence curve increases primarily during the fifth and sixth decades of life.

In their recent study, FitzGerald and colleagues viewed incidence in the opposite way: They estimated the frequency of BRCA1 mutations in women who develop breast cancer at a young age. They recruited 418 women who were 40 years of age or younger in whom breast cancer had been diagnosed between 1981 and 1992. The BRCA1 gene was analyzed in a subgroup of 30 women in whom breast cancer developed before 30 years of age. Screening for the 185delAG mutation was conducted among the 39 Jewish women who developed breast cancer.

Forty percent of the entire group had at least one first- or second-degree relative who had developed breast cancer, although only 7% had a family pedigree with several affected relatives (which would suggest a specific genetic defect). Four of the 30 women who developed breast cancer before 30 years of age (13% [95% CI, 4% to 31%]) had BRCA1 mutations that resulted in unambiguous inactivation of a gene product. Seven had mutations that seemed clinically unimportant. Eight of the 39 Jewish women who developed breast cancer before 40 years of age (21% [CI, 9% to 36%]) had the 185delAG mutation. None of these women had a strong family pedigree for breast cancer, although 7 had at least one affected first- or second-degree relative.

In light of these data, clinicians might be tempted to perform BRCA1 testing, which is clinically available, on young Jewish women or any young woman who has several family members with breast cancer (especially if cancer developed at an early age). This logic, however, is problematic.

First, testing is difficult at best. More than 125 mutations have been found on BRCA1, and more than 65 have been found on BRCA2. The clinical significance of each mutation has not been fully elucidated. Moreover, the natural history of cancers associated with mutations on these genes is still unknown. Second, an appropriate preventive strategy has not been developed. Should intensive mammography be done among women in their 30s? Would bilateral mastectomies be suggested? For prevention of ovarian cancer, a strategy would be even more difficult to design.

Third, social discrimination would not be uncommon if testing revealed a mutation. In the 1980s, cases of insurance or employment bias against women who carried mutations were reported anecdotally [1]. With the explosion in genetic research since then, the number of carriers has increased and would increase further if testing were made commonplace. Finally, decisions are very complex because genetic counseling involves counseling both a patient and her family. In a recent study [2] of 279 members of families with strong histories of breast and ovarian cancer, only half of the members wanted to know the results of BRCA1 testing. In addition, it is likely that BRCA1 mutations will soon be identifiable in fetuses, an advance that will create even more ethical confusion.

Papanicolaou Smear Was Not Helpful after Hysterectomy

Fetters MD, Fischer G, Reed BD. Effectiveness of vaginal Papanicolaou smear screening after total hysterectomy for benign disease. JAMA. 1996; 275:940-7.

A more clear-cut prevention strategy than breast cancer screening has been the use of the Papanicolaou smear for cervical cancer screening. In 1950, cervical cancer was the most common cause of cancer-related death in women. It is now the eighth most common. Almost all of this decline can be attributed to the routine use of Papanicolaou smears. In recent years, a consensus on how often the test should be done has been increasing. For example, the American College of Obstetrics and Gynecology guidelines state that all women who are or have been sexually active, or who have reached the age of 18 years, should undergo an annual Papanicolaou test and pelvic examination. After a woman has had three or more consecutive examinations with normal results, Papanicolaou smears may be performed less frequently (3 years between tests is common).

However, it has been unclear what should be done about women who have had hysterectomy. This is a large group: The lifetime incidence of hysterectomy is about 30%, and 85% of operations are performed for benign conditions. Almost all hysterectomies in the United States involve the removal of all cervical tissue, leaving only vaginal tissue intact. Thus, Papanicolaou smears done in women who have had this surgery are actually screening tests for vaginal cancer. An estimated 5.72 million smears a year are done on such women.

In a systematic review of the medical literature published from 1966 through 1995, Fetters and colleagues assessed the effectiveness of screening for vaginal cancer in women who have had total hysterectomy for benign disease. After combining the results of the two well-done cohort studies, the authors found that among 1472 women followed for 5 to 15 years, 2 had vaginal dysplasia and none had developed vaginal cancer. These data, along with other research, suggest that vaginal dysplasia rarely progresses to vaginal cancer. In turn, vaginal cancer is rare, with an estimated incidence much lower than 1 case per 100 000 women. Papanicolaou smears are insensitive for detecting vaginal carcinoma after total hysterectomy. The positive predictive value of the test in this population has been estimated to be less than 1% [3].

This careful and thorough review found no evidence to recommend routine screening of vaginal smears in women who have had total hysterectomy for benign disease. Soon after this article was published, Pearce and colleagues [4, 5] reported on a cohort study of almost 10 000 women; their findings confirmed the estimates provided by Fetters and colleagues.

Specific Programs Improved Academic Parity

Fried LP, Francomano CA, MacDonald SM, Wagner EM, Stokes EJ, Carbone KM, et al. Career development for women in academic medicine: multiple interventions in a department of medicine. JAMA. 1996; 276:898-905.

Forty-two percent of medical students, 34% of residents, and 26% of full-time medical school faculty are women [6]. Only 10% of full professors are women, and only five medical schools have female deans. A survey of academic pediatricians found that women were more likely than men to spend time taking clinical care of patients and to partake in educational endeavors; this finding was strongly related to lack of advancement in academic medicine [7]. However, some progress is being reported in this area.

Fried and colleagues reported on interventions implemented from 1990 to 1995 in the Department of Medicine at the Johns Hopkins University in Baltimore, Maryland. All full-time faculty members were surveyed; on the basis of the results and with the support of department leaders, several programs were developed to achieve the following goals: retain excellent female faculty, attain salary equity for men and women, and promote women so that the proportion of women at the associate professor level is equal to the proportion of men at that level. Interventions to achieve these goals included educating faculty about sex bias in academic medicine, decreasing the isolation of female faculty by scheduling meetings and conferences during the standard workday, and increasing the presence of women as speakers and committee leaders. Faculty development was promoted through yearly faculty reviews and mentoring.

At the end of the study period, the number of women at the associate professor level or above had increased fivefold. Interim survey results (comparing attitudes in 1993 with those in 1990) showed that almost twice as many women expected to be in academic medicine in 10 years. Both female and male faculty reported improvements in the timeliness of promotions, access to information needed for faculty development, mentoring, and salary equity.

If department leaders strongly support such interventions (which were based on specific needs), they can benefit all faculty. The lessons could be used at other academic, and perhaps nonacademic, institutions.

Perimenopause

Perimenopause remains one of the least well-understood parts of the female life cycle. Evidence remains sparse, but research attempts are increasing dramatically. Much attention, especially in the lay press, has recently been given to phytoestrogens, weakly estrogenic compounds derived from plants.

Evidence Supported the Effects of Phytoestrogens

Knight DC, Eden JA. A review of the clinical effects of phytoestrogens. Obstet Gynecol. 1996; 87(5 pt 2):897-904.

Perimenopause-or transmenopause-is a process, not an event. It lasts 2 to 10 years. The hall-mark is abnormal bleeding and other physical signs; emotional distress is common, however, and is too often ignored. Some success in blunting emotional distress has been reported with the use of anxiolytic agents, especially buspirone, which was initially promoted for premenstrual symptoms. Antidepressants are commonly used, but their effectiveness remains to be proven.

Treatment of menstrual irregularities during the menopause transition remains extremely controversial. In the past, the irregular menses associated with menopause were often treated with oral contraceptives. However, the synthetic estrogens common to all oral contraceptives are associated with many adverse effects, especially an increased risk for thromboembolic events. The most common treatment regimen is probably conjugated estrogen, 0.625 mg/d, taken every day, with medroxyprogesterone, 2.5 mg/d, taken for 14 days each month. This regimen regularizes the menstrual cycle; if used too early in the perimenopause process, however, it may increase estrogen levels and cause vague feelings of illness. Gynecologists commonly start this regimen when follicle-stimulating hormone levels exceed 30 IU/mL or when estradiol levels are consistently less than 20 to 30 pg/mL.

The use of selective estrogen receptor modulators, similar to tamoxifen, may be promoted within the next year or two as hormone replacement therapy that does not induce bleeding. Clinical trials of this approach are in progress.

In response to the claim that the clinical effects of phytoestrogens are superior to and safer than the effects of other estrogens, Knight and Eden reviewed research on the effects of phytoestrogens in humans. They found 861 articles, ranging from case reports to clinical trials. Evidence was found to support the claims that phytoestrogens are biologically active, and epidemiologic (observational) research supported the hypothesis that phytoestrogens inhibit the development and spread of cancer. Ingestion of food that contains such phytoestrogens as soy are associated with lower cholesterol levels and higher bone density.

Although the evidence in this review is not strong, the available data suggest that phytoestrogens help protect vegetarians against cancer and heart disease. Intervention studies are needed to assess the clinical effects of phytoestrogens before clinical recommendations can be made.

The Mature Years

The usual approach to treating arthritis has been prescription of medication; however, alternative interventions, such as exercise, may also be effective. Arthritis is a major chronic illness in women, yet few research efforts have been directed toward the social, economic, and psychologic impact of this disease on women. Arthritis disproportionately affects women: About 22 million U.S. women and 56% of women 65 years of age and older have the condition. Urinary incontinence is also extremely common among older women, and recent research has revealed some reversible risk factors. Finally, 1996 saw the publication of more research findings that favor the use of estrogen replacement therapy.

Exercise Improved Outcomes of Osteoarthritis

Ettinger WH Jr, Burns R, Messier SP, Applegate W, Rejeski WJ, Morgan T, et al. A randomized trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis. The Fitness Arthritis and Seniors Trial (FAST). JAMA. 1997; 277:25-31.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the traditional first-line therapy for osteoarthritis, although rheumatologists frequently recommend acetaminophen. Exercise has been downplayed because it was feared that patients would be prone to repetition injuries that might exacerbate disease in weight-bearing joints.

In an 18-month clinical trial, Ettinger and colleagues sought to determine the effects of structured exercise programs on self-reported disability in older adults with osteoarthritis of the knee. They enrolled 439 adults 60 years of age or older who had radiographically evident osteoarthritis of the knee, pain, and self-reported physical disability. Participants were randomly assigned to an aerobic exercise program, a resistance exercise program, or a health education program. The exercise programs began as classes of 10 to 15 participants who met for 1-hour sessions three times a week for 3 months. Thereafter, the programs were home-based. Aerobic exercise consisted of walking, and resistance exercises primarily comprised strengthening calisthenics. Outcomes were self-reported disability, knee pain, measures of physical function, radiographic abnormalities, aerobic capacity, and quadriceps strength.

Both exercise regimens resulted in decreased disability, reduced pain, and increased ambulation and performance scores. Exercise was associated with significant clinical improvement at reasonable cost. The authors suggest that a good clinical approach would be collaboration between clinicians and exercise leaders to provide at least short-term exercise training. Such a simple program could have a major impact on disability in individual patients and in the population at large.

Rheumatoid Arthritis Responded to Early Aggressive Treatment

van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AM, van Booma-Frankfort C, van der Veen MJ, et al. The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial. Ann Intern Med. 1996; 124:699-707.

As stated above, women are disproportionately affected by arthritis. The traditional approach to rheumatoid arthritis has been to begin treatment with NSAIDs, including aspirin. For patients who do not adequately respond to NSAIDs, the next step has been to use disease-modifying antirheumatic drugs (DMARDs). Recently, however, many rheumatologists have been moving to earlier use of DMARDs. Van der Heide and colleagues compared these two therapeutic strategies.

In an open clinical trial, 238 consecutive patients with recently diagnosed rheumatoid arthritis were randomly assigned to receive either early or delayed treatment with DMARDs. Outcome measures were functional disability, pain, joint score, erythrocyte sedimentation rate, and progression of radiologic abnormalities.

Functional disability, pain, and joint score over 1 year improved significantly more in the early DMARD treatment group than in the delayed treatment group. Radiologic abnormalities progressed at an equal rate, although the study may have been too short to detect an effect. Therapy was discontinued because of adverse effects in 29% of patients in the delayed treatment group but in only 8% of patients in the early treatment group.

The results suggest that DMARD therapy should begin earlier and that internists probably should become better versed in the use of these drugs or should refer patients to a rheumatologist early. In fact, it may be more efficacious for primary care physicians to focus their energies primarily on diagnosing rheumatoid arthritis, which can be difficult. In one study, the diagnosis took a median of 36 weeks in primary care settings [8].

Obesity and Hysterectomy Were Risk Factors for Incontinence

Brown JS, Seeley DG, Fong J, Black DM, Ensrud KE, Grady D. Urinary incontinence in older women: who is at risk? Study of Osteoporotic Fractures Research Group. Obstet Gynecol. 1996; 87(5 pt 1):715-21.

Urinary incontinence affects 25 million Americans, mostly women. It is a common reason for institutionalizing elderly persons, and as many as 50% of nursing home residents are incontinent. Americans spend $10 billion annually on incontinence. Such products as disposable pads and adult diapers tend to give patients a sense of security, but they may promote the belief that incontinence is a condition that patients have to live with. This attitude may deter patients from seeking medical evaluation, even though a very large proportion of persons with incontinence can be helped or cured.

Incontinence is usually one of two types. The first, urge incontinence, is an involuntary loss of urine associated with a strong desire to void. Patients with this type of incontinence report that they cannot reach the bathroom in time. The second type, stress incontinence, usually involves leakage of urine when intra-abdominal pressure is increased as a result of coughing; sneezing; or, less frequently, laughing and exercising. Most women have mixed incontinence. Elderly women with urinary tract infections often present with symptoms of urge incontinence. In addition, 20% of women with bladder cancer present with the symptoms of urge incontinence.

Brown and colleagues, who are primarily studying osteoporosis on an epidemiologic basis, used their data to estimate the prevalence and severity of urinary incontinence in older women and identify factors associated with the occurrence of incontinence. In a cross-sectional questionnaire study involving 7949 community-dwelling women, the authors assessed these findings during clinic visits occurring from 1992 through 1994.

Urinary incontinence was reported by 41% of respondents. An unsurprising finding was that age was a major risk factor (odds ratio, 1.3 per 5 years [CI, 1.2 to 1.5]). The Table 1 shows other major risk factors found in a multivariate analysis. When the researchers combined odds ratios with prevalence, they found that obesity accounted for 16% of cases of daily incontinence and that hysterectomy accounted for 14%.

Urinary incontinence is perhaps the most common chronic medical condition in older women. However, many risk factors can be modified to decrease the prevalence. Obesity can be treated, for example, albeit with difficulty. In addition, these findings point to a reassessment of the indications for hysterectomy, the second most frequently performed surgery in the United States.

In the medical office, we can teach patients the bladder drill, which can decrease the severity of mild urge and stress incontinence. The basic principle is increasing the time to voiding. We instruct women to void approximately every hour whether they need to or not. They can then slowly extend the interval so that by 5 weeks they void every 3 to 4 hours. They are told that, if possible, they should resist voiding when they have the urge. Patients who go through the bladder drill achieve a 50% to 90% improvement in their symptoms.

Similarly, Kegel pelvic floor exercises diminish the episodes of stress incontinence by strengthening the levator muscles. These exercises involve sets of short and long contractions of the pelvic floor muscles two to three times a day. However, if the clinician simply tells patients to do Kegel exercises, only 30% will actually do the exercises correctly. The most effective time to instruct a woman is the bimanual examination, during which the examiner can determine whether the contractions are correct. Patients can also be referred to incontinence specialists and receive biofeedback or intravaginal pressure probes to maximize the Kegel maneuver. When Kegel exercises are done properly and regularly, up to 80% of women report major improvement by 12 weeks.

The pessary has been used for decades for stress incontinence, particularly for incontinence associated with exercise. Many tampon-like devices based on the same principle of the pessary are now marketed, but their efficacy is unknown. Surgery is a last resort, and success rates vary considerably among surgeons.

Anticholinergic medications, such as oxybutynin and imipramine, may help reduce bladder spasms and urge incontinence. However, 50% of women have clinically significant side effects, including constipation, dry mouth, and blurry vision. No evidence suggests that estrogen therapy improves incontinence symptoms.

Cardiovascular-Related Mortality Rates Decreased with Dual Regimen

Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996; 335:453-61.

In recent years, much of the discussion of hormone replacement therapy focused on hot flashes and bone maintenance. In 1996, however, researchers reported that estrogen affects almost every organ. Despite a few exceptions, there now is little doubt that estrogen replacement is beneficial in many ways for most older women. A major concern has been that the protective effect of estrogens on heart disease would be reduced or eliminated by the addition of progestins, which blunt estrogen's beneficial effect on lipids.

The Nurses' Health Cohort consists of more than 50 000 women. Grodstein and colleagues sought to determine the effect of combined hormone replacement on cardiovascular disease in this large group. The cohort, whose members ranged from 30 to 55 years of age at baseline, were followed for 16 years. Information on health and medication use was gathered through biennial questionnaires. During the study period, 1.6% of the cohort had myocardial infarction or died of coronary artery disease, and 1.0% had stroke.

These researchers found a marked decrease in the risk for major coronary artery disease among women taking combined hormone replacement therapy compared with those not taking hormones (relative risk reduction [RRR], 61% [CI, 22% to 81%]). This reduction was similar to the decrease seen with estrogen alone (RRR, 40% [CI, 17% to 57%]). However, Grodstein and colleagues did not find that estrogen or combined therapy protected against stroke. Once women discontinued therapy, the protective effect dwindled to almost zero by 10 years after cessation of hormone therapy.

It is reassuring to learn that a longtime concern about hormone replacement therapy has been at least somewhat reduced, although this evidence is observational and thus not definitive.

Alzheimer Dementia Was Blunted

Tang M, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, et al. Effect of estrogen during menopause on risk and age at onset of Alzheimer's dementia. Lancet. 1996; 348:429-32.

Estrogen affects the brain in many ways, including promotion of the growth of cholinergic neurons. It may also decrease amyloid deposition. In a prospective cohort study, Tang and colleagues investigated whether estrogen taken after menopause delays the onset of or prevents Alzheimer dementia. The researchers recruited 1124 elderly female New York residents (mean age, 74.2 years) who had no evidence of dementia. Detailed health questionnaires were administered, and follow-up ranged from 1 to 5 years.

About 12.5% of women reported using estrogen. The relative risk for developing Alzheimer dementia was reduced in the estrogen group (5.8% compared with 16.3% in the group not using estrogen; RRR, 60% [CI, 15% to 78%]). The number of women needed to treat with estrogen to prevent one case of disease was about 10. The longer estrogen was taken, the lower the risk for developing Alzheimer dementia.

This study supports the findings of retrospective studies. A larger prospective study is now being done; if this ongoing study confirms the protective effects of estrogen against Alzheimer dementia, this finding could be one of the great medical advances of recent years.

A review of the evidence suggests that the case for postmenopausal estrogen looks good. The lifetime risk for heart disease in women is 46%. The cumulative lifetime risk for Alzheimer dementia approaches 50%. The lifetime risk for sustaining a hip fracture, the principal focus of estrogen therapy in previous years, is only 15%. Therefore, the benefits of hormone replacement seem to be much greater than most of us have appreciated.

On the negative side, long-term use of estrogen may confer an increase in the risk for breast cancer as great as 30%, although this Figure is controversial. Of course, unopposed estrogen greatly increases the risk for endometrial cancer, but the risks for uterine cancer seem to be largely negated by the addition of progestins.

Yet, few women take estrogens. In 1992, only about 20% of eligible women were receiving the hormone. In a recent survey of older women, Salamone and colleagues [9] found that the primary reason women stopped taking hormone replacement was the patients' belief that they no longer needed it. The main barriers to starting a hormone replacement regimen were fear that the hormone would cause harm. Physicians face a major task in educating patients about the actual risks and benefits.

Social Health Risks

Finally, an Update in women's health would be incomplete if it ignored the social issues that affect the health of women and their children. In 1996, one of the most important pieces of legislation in 40 years was signed into law. President Clinton said that the Personal Responsibility Act of 1996 "will end welfare as we know it." The law eliminates Aid to Families with Dependent Children. That program, created in 1935, was a safety net for the poor. More than 90% of recipients were women and children. The 1996 welfare law also cut the supplemental security income program, the food stamp program, and last-resort health benefits to illegal immigrants.

These sweeping legislative changes will have enormous consequences for poor women, who have been asked to immediately begin looking for work. In addition, the Urban Institute, even using optimistic assumptions, estimates that the bill will move 2.6 million people, including 1.1 million children, into poverty [10]. Moreover, the lifetime maximum duration of support is now no more than 5 years.

At minimum wage, workers will make about $10 000 a year. Because they will have income, most will no longer be eligible for Medicaid benefits. Their low-wage jobs will rarely carry health benefits. Some estimate that more than 3 million children and 1 million women will be added to the uninsured population in the next 5 years, with obvious and potentially ominous health consequences.

Dr. Ness: Department of Medicine, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261.

Dr. Hendrix: Department of Obstetrics and Gynecology, Wayne State University, 4707 St. Antoine, Detroit, MI 48201.

Dr. Roberts (Series Editor): Madrona Medical Group, 4370 Cordata Parkway, Bellingham, WA 98226-8075.